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Endocrinology & Cancer. Endocrinology 317/319 Department of Biology University of Massachusetts Boston Kenneth L. Campbell & Victoria Del Gaizo Moore. Overview of main points to be covered:. Cell Cycle Control What can go wrong Stages of Cancer Development Specific Examples of Cancers.

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Endocrinology & Cancer

Endocrinology 317/319

Department of Biology

University of Massachusetts Boston

Kenneth L. Campbell


Victoria Del Gaizo Moore

overview of main points to be covered

Overview of main points to be covered:

Cell Cycle Control

What can go wrong

Stages of Cancer Development

Specific Examples of Cancers


Oncogenesis - Chemical Signaling and Cancer

  • Basic Concepts
  • Tumor
    • Benign (self contained)
    • Malignant (migratory, prone to seeding tumors at other sites)
    • Hypertrophy - hypertrophic cells; hyperplastic tissue
    • Neoplasia - new, often irregular, growth or tissue
  • Proto-oncogenes = Normal gene precursors of oncogenes I V Mutational AgentsI V
  • Oncogenes = Gene associated with abnormal cell growth
  • Oncogene Product = Expressed protein coded by an oncogene
  • Mutagens
    • Radiation, Chemical - tend to be small changes, insertions, deletions, or base changes
    • Chromosome Rearrangements (in meiosis) - can be large changes, deletions, inversions
    • Viral Rearrangement - viruses can become lysogenic & excise & carry genes or foreign promoter DNA to subsequent cellular hosts where these insert into non-homologous sites & are expressed in a non-regulated or inappropriately regulated fashion, often leading to oncogenesis via disruption of the normal events of the cell cycle or cell cycle regulatory points.

Normal Cell Cycle & Controls


p53, p21

route to apoptosis

role of DNA repair


Normal Stages of Mitosis shown

by time.

Cells receive cues from their

environment (surrounding cells

and tissues) that help direct it

to undergo division

Each cell must monitor DNA

replication to make sure that synthesis is correct, fixing any mistakes along the way.


During DNA replication the two strands are copied in opposite directions using different methods. Topoisomerase is also involved and makes cuts in one or both strands that must be ligated to maintain sequence integrity. Thus, there are opportunities for sequence mismatches or replication mistakes even during mitosis.


The anti-parallel, helical, frequently coiled and supercoiled nature of DNA within cells presents topological problems during replication that can result in mistakes that must be monitored by the cell cycle machinery.


pRB- retinoblastoma protein

named so because in retinoblastoma cancer both alleles of

the gene are mutated so no protein is produced

pRb prevents the cell from dividing or progressing through

the cell cycle when DNA is damaged.

Control occurs at S (DNA synthesis phase) because

pRb binds and inhibits transcription factors of the E2F family

When pRb is ineffective at this role, mutated cells

can continue to divide and may become cancerous.


pRB regulation depends on phosphorylation

pRb can actively inhibit cell cycle progression when it is dephosphorylated

Therefore phosphorylation inactivates its function.

At the end of mitosis (M phase) pRB depends on a phosphatase to dephosphyorylate it, allowing it to bind to E2F


pRb the Master Controller:

The First Checkpoint

Robert A. Weinberg, How Cancer Arises, Scientific American 275(3):62-70, September 1996.


Phosphorylation of pRb by cyclin/cyclin-kinase complexes allows release of pRb-bound transcription factors such as E2F. Now free, the transcription factors can alter expression of genes necessary for cell growth and DNA synthesis.

Rachel A. Freiberg, Susannah L. Green, Amato J. Giaccia

Hypoxia and Cell Cycle

In: Cell Cycle Checkpoints and Cancer

Mikhail V. Blagosklonny, Ed.ISBN: 1-58706-067-1


Human Papilloma Virus, HPV, perturbs the pRb checkpoint allowing cells to enter S Phase under conditions that may not be optimal or safe for DNA synthesis or cell replication.

Hoenil Jo, Jae Weon Kim, Implications of HPV infection in uterine cervical cancer,

Cancer Therapy 3: 419-434, 2005

Sequential phosporylation of Rb by cyclin/cdk complex inhibits the repressor activity of pRb. The HPV E7 binds to the hypophosphorylated form of the pRb proteins. This binding disrupts the complex between pRB & the cellular transcription factor E2F, resulting in the liberation of E2F, which allows the cell to enter the S phase of the cell cycle.


p53, p21 & The Second Checkpoint

Robert A. Weinberg, How Cancer Arises, Scientific American 275(3):62-70, September 1996.


Hypoxia, cellular exposure to reactive oxygen species, mitochondrial damage, or direct damage of DNA by chemicals or radiation can stimulate p53 actions that halt cell division, activate DNA repair mechanisms, &/or stimulate the cell to undergo apoptosis (programmed cell death). This protects the organism from clonal expansion of mutated cells.

Olivier Pluquet, Pierre HainautGenotoxic and non-genotoxic pathways of p53 induction

Oncoserve Online, 2004 Oncoserve Online p53.mht


Hoenil Jo, Jae Weon Kim,

Implications of HPV infection in uterine cervical cancer

Cancer Therapy 3: 419-434, 2005

HPV infection also perturbs the second, p53, checkpoint preventing p53 from diverting cells with damaged DNA toward cell cycle arrest or cell death. Damaged cells can then proliferate unchecked.

DNA damage induces p53 activation, leading to either cell cycle arrest or apoptosis. The HPV E6 binds to E6-AP & redirects it to p53, which results in the E6-AP-mediated ubiquitination & rapid proteasomal degradation of p53.


RB/p53 Interactions To Regulate Cell Cycle & Apoptosis

Cell cycle transition from G1-S phase is mediated by Rb interactions with the E2F transcription factor family, an important regulator of the cell cycle. Growth factors lead to phosphorylation of Rb in late G1 phase by cdk/cyclin. This is followed by release of E2F, allowing transcriptional activation of E2F target genes; this promotes S-phase entry & cell proliferation. HPV E7 & Simian Virus 40 (SV40) promote release of E2F from Rb. In contrast HPV E6 & the dominant negative, DN-p53 inhibit p53 activity leading to cell proliferation.

Shehata, Cancer Cell International 2005 5:10   doi:10.1186/1475-2867-5-10



Summary of Cancer and Cell Cycle:

Carcinogenesis seems to be a multistage process where normal cells

progress to cancer through a gradual accumulation of genetic errors.

This has led to the hypothesis that cancer may be caused by mutations

that cause genetic instability.

Cell cycle controls, checkpoints, maintain the genetic stability of dividing


There are at least two important known checkpoints, located in G1/S

and G2/M involving tumor suppressors Rb and p53, respectively.

p53 is activated by DNA damage.

During carcinogenesis, these checkpoints fail to prevent abnormal cells

from going through the cell cycle.


Extracellular factors may alter the status of the pRb checkpoint & thereby change transcriptional activities.


Disruption of the cell cycle can result in replication of cells with:

damaged DNA

increased susceptibility to further DNA damage

ability to avoid apoptosis

ability to avoid immune surveillance

activated telomerase



Gene mutation, gene movement, or change in regulatory sequences or position




Mechanisms of DNA damage/mutation

chemical – reactive agents, reactive oxygen species, environmental agents


replication damage – translocations, deletions, insertions

viral insertion/excision


Oncogene: modified gene that is believed to cause cancer

  • The proto-oncogene can become an oncogene by a relatively small
  • modification of its original function. There are three basic activation types:
  • A mutation within a proto-oncogene can cause a change in the protein structure, causing
    • an increase in protein (enzyme) activity
    • a loss of regulation(pRB)
  • An increase in protein concentration, caused by
    • an increase of protein expression (through misregulation)(BCL-2 with miRNA’s)
    • an increase of protein stability, prolonging its existence and thus its activity in the cell
      • a gene duplication (one type of chromosome abnormality), resulting in an
      • increased amount of protein in the cell
  • A chromosomal translocation (another type of chromosome abnormality), causing
    • an increased gene expression in the wrong cell type or at wrong times
    • the expression of a constitutively active hybrid protein. This type of aberration in a
    • dividing stem cell in the bone marrow leads to adult leukemia(BCL-2 with t(14;18))

Apoptotic Pathways: All roads lead to mitochondria

  • Extrinsic
    • Extracellular signals cause intracellular changes
    • Caspase activation (8), eventually leads to mitochondria
  • Instrinsic
    • Starts with signals within the cell
    • Caspase activation (9 and 3), Cytochrome c release


  • comparable to levels found in follicular lymphoma and H2 cells, which have a t(14;18)



BCL-2, a different kind of oncogene

BCL-2 was originally discovered in Follicular Lymphoma patients

a chromosomal translocation between chromosomes 14 and 18 placed

BCL-2 under constitutive control of Ig heavy chain

results: much BCL-2 protein is made all of the time in these cells

This was the first time where a mutation that caused a protein to be overexpressed caused cancer (in the past only down-regulation models were known, like pRB)

In Chronic Leukemia BCL-2 is also overexpressed, despite the absence of t(14;18)

microRNAs are responsible for BCL-2 overexpression in these cancers

loss of mir15 and 16 cause uncontrolled BCL-2 protein expression

Del Gaizo Moore, et al. JCI 2007


How does BCL-2 overexpression lead to cancer?

There are pro and anti-apoptotic proteins

those that promote and those that oppose cell death

BCL-2 is an anti-apoptotic protein

DNA damage, environmental stress, or other cellular stresses cause death signaling

molecules to be expressed.

These death signals are able to be bound up by BCL-2.

In a normal cell with regular amounts of BCL-2, the BCL-2 gets “full” of death signals

Easily and there are excess death molecules to trigger apoptosis

BUT, if a cell has extra BCL-2 then it can absorb ALL of the death molecules

thereby preventing cell death


Normal cell

BCL-2 overexpressing cell



- death signals

- other proteins bound to BCL-2

- cytochrome c

- BCL-2 protein

- BAX/BAK protein


Genes often involved in cancer formation, are

hot-spots for primary or secondary mutations

Tumor Suppressors




Transcription Factors



inappropriately controlled cell replication leading to disruption of normal physiology, metabolism or structure ultimately disrupting homeostasis irreversibly


new cell growth; may be benign (not unlimited or invasive) or malignant (cancerous leading toward metastasis)

Hypertrophy – elevated size, for cell or tissue

Hyperplasia – elevated cell number


Path to Cancer:

Completion is rare due to endogenous controls & mechanisms!

Induction/Initiation/primary mutation

– fixation into the genome

-- avoidance of apoptosis

-- avoidance of immune rejection


– stimulation of cell expansion of mutated clone

-- continued avoidance of apoptosis

-- continued avoidance of immune surveillance


-- epigenetic &/or secondary mutations

-- immortalization, activation of telomerase

-- loss of cell contact inhibition

-- angiogenesis of primary tumor


-- tertiary mutations

-- outgrowth of tumor


-- breach of vascular endothelium

-- lodging & binding to capillary beds

-- invasion of secondary sites


Changes in Cancer

These range from the molecular through cellular & organ levels to the entire organism. What begins in a single cell, possibly even a single alteration of one chemical bond, ultimately manifests as a terminal physiological imbalance for the host organism. This might be termed the “Butterfly Effect” in cancer.

Fabio Grizzi, Maurizio Chiriva-Internati,

Cancer: looking for simplicity and finding complexity, Cancer Cell International 2006, 6:4, doi:10.1186/1475-2867-6-4.


James E. Trosko, Randall J. Ruch, Cell-cell communication in carcinogenesis, Frontiers in Bioscience, 3, d208-236, 2/15/1998.

Schematic of the route from a tissue stem cell through the process of mutation & clonal expansion to malignancy


James E. Trosko, Randall J. Ruch, Cell-cell communication in carcinogenesis, Frontiers in Bioscience, 3, d208-236, 2/15/1998.

Mathematical model of the route from a normal cell through the various steps & processes leading to overt cancer


Ball diagram of Nowell's hypothesisGreen balls represent cells that have developed a genetic abnormality & are expanding or growing into a clone of cells. One of these cells develops a 2nd genetic abnormality, blue ball. This then expands into its own clone of cells, subclones of the green population. A third genetic mistake, dark red ball, leads to clonal expansion of a sub-subclone. Eventually, a genetic mistake is made in one of the cells of the subclones or sub-subclones that allows that cell to spin off a cancerous subclone.

The site was funded by AstraZeneca LP through an unrestricted educational grant to theRyan Hill Research Foundation, Seattle, WA


Another schematic of carcinogenesis emphasizes the early steps in tumor formation including the role of cellular repair & suppression of apoptosis but fails to note the importance of secondary or tertiary mutations in allowing clonal expansion, evasion of immune suppression, & establishment of unlimited growth potential.

Where might those occur?

James E. Klaunig, Lisa M. Kamendulis, Yong Xu, Epigenetic Mechanisms of Chemical CarcinogenesisDivision of Toxicology, Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN


Another schematic emphasizing the cellular stages in carcinogenesis, cellular mutation, & agents that may be involved in the various steps.


This depiction of the steps in the in vivo process compares these changes with what occurs during the in vitro transformation of cells grown in tissue culture.

Cell Transformation Assays as Predictors of Human Carcinogenicity

The Report and Recommendations of ECVAM Workshop 391-3

ATLA27: 745-767


The upper row represents disturbances in growth, differentiation, & tissue integrity that lead to the phenotypes that characterize the different stages of cancer, shown in the lower row. Multiple genetic alterations underlie cancer development, including oncogene activation & tumor suppressor loss of function.



Note that even in well developed experimental models we still lack clear markers or unique triggers for the Promotion & Progression stages of carcinogenesis.

Zbigniew Walaszek, Margaret Hanausek, Thomas J. Slaga, Combined natural source inhibitors in skin cancer prevention, Cellscience Reviews 1(3), ISSN 1742-8130.


This description comes a bit closer to what has been observed; there still is obvious discussion of which molecular or cellular events contribute specifically to the Promotion, Progression, Conversion/ Transformation, Invasion/ Metastasis steps.


The interaction of carcinogens with cells that can lead cells toward formation of malignant tumors.

Note the multiple points at which a carcinogen or cells damaged by a carcinogen may be eliminated or repaired.

Tobacco smoking and cancer: The promise of molecular epidemiology

Sophia S. Wang, B.S., Jonathan M. Samet, M.D., M.S.

Salud Publica Mex 1997;39:331-345.


Carcinogen exposure is not simply the amount of compound applied to an organism but the amount to which the reactive molecules in target cells are exposed, moreover, multiple steps of response are involved in activation of cancer.

Department Of Genetic Ecotoxicology, Institute of Experimental Medicine,Academy of Sciences of the Czech Republic


A correlation of the events in carcinogen metabolism with the stages of cells moving toward clinical disease

Tobacco smoking and cancer: The promise of molecular epidemiology

Sophia S. Wang, B.S., Jonathan M. Samet, M.D., M.S.

Salud Publica Mex 1997;39:331-345.


Besides losing the ability to correctly determine if their environment is appropriate for division & the characteristics necessary for the immune system to remove them as damaged cells, cells on the path to tumor & cancer formation also gain several capacities: they evade apoptosis, produce their own growth factors, become insensitive to growth suppressors & cell contact signals, gain telomerase activity & overcome the Hayflick limit, & express angiogenic factors & molecules needed during metastasis.

Douglas Hanahan & Robert A. Weinberg, The hallmarks of cancer,

Cell 100:57–70, 2000.


The multi-step nature of carcinogenesis is again emphasized when chronic inflammation seems involved in initiation

Figure 1 Inflammatory-epithelial interactions in multi-step carcinogenesis

Moss SF and Blaser MJ (2005) Mechanisms of Disease: inflammation and the origins of cancer.Nat Clin Pract Oncol 2: 90–97 10.1038/ncponc0081


The process also remains similar when chronic infection with a viral agent, e.g., HPV is involved.

Céline Delloye, Elodie Gautier, MichèleOttmann, Epidémiologie et oncogénèse liées aux infections par les Papillomavirus, Virologie Etudiants M1 ENS Lyon.mht


Eva Szabo & Gail L. Shaw

A Specific Disease: Lung Cancer



Tumor Suppressor Genes as Initiation Targets

Mutation or deletion of tumor suppressor (TS) genes may initiate many forms of cancer. For tumors to develop, both alleles of the TS gene must be inactivated. In familial cancer syndromes, a mutant allele of a TS gene is inherited and is present in every cell (e.g. p53 in Li Fraumeni). But, tumorigenesis is not initiated until the second allele is inactivated in a somatic cell. In non-familial cases, inactivation of both alleles occurs via somatic mutation or deletion. The end result is the same in both cases, the lack of a functional TS gene leads to tumor development.


Philadelphia Chromosome Formation:

Classic Case of Chromosomal Rearrangement in Carcinogenesis

Rearranged chromosomes: the c-abl oncogene from the distal tip of chromosome 9q34 when translocated to the bcr (break-point cluster region) locus on chromosome 22q11.2 forms the t(9;22) translocation found in >95% of CML, chronic myelogenous leukemia. It generates a chimeric gene that expresses a chimeric bcr-abl mRNA & fusion protein that localizes to the cytoplasm & remains constitutively active in phosphorylating STAT-5 & suppressing apoptosis.




Conversion, Transformation



Expression of angiogenic factors, e.g., VEGF forms, promote vascularization of tumors & establish the routes by which metastasis-capable tumor cells may reach the blood supply & secondary tumor sites.


Receptor-binding specificity of VEGF family members & VEGFR-2 signalling pathways

The multitude of VEGF forms along with the number of available receptors & linked transduction pathways demonstrate the wide range of effects tumor expression of these factors may have on both tumor cells & their surrounding tissue cells.

Hiroyuki Takahashi, Masabumi Shibuya, The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions,Clin. Sci. (2005) 109, 227-241Clinical Science


Events leading to angiogenesis and metastasis



Initial tumor,

distal to vasulature,

becomes hypoxic

Early tumors are small, <1 mm3 in diameter. Without angiogenesis tumors cannot grow further even though active cell division counter-balanced by apoptosis continues to occur. Tumor cells most distal to blood supply become hypoxic & produce hypoxia inducible factor-1α (HIF-1α) which accumulates in the cytoplasm & translocates to cell nuclei. This promotes transcription of many target genes, including that for vascular endothelial growth factor (VEGF). Thus, an angiogenic switch is activated that stimulates formation of the new vascular necessary for tumor growth. Tumor cell/stromal cell/endothelial cell interactions cause secretion & activation of matrix metallo-proteinases (MMPs) that degrade the extracellular matrix and permit budding of new blood vessels from existing vessels. Proliferation & migration of vascular endothelial cells are triggered by angiogenic factors secreted by tumor cells, such as VEGF & basic fibroblast growth factor (bFGF). Blood vessels established within tumors permit invasion of tumor cells into the bloodstream where they are carried to additional sites in the body. If they become attached or lodged, & invade the local blood vessels, they may then establish new tumors or metastases.


Generation of the Mutator Phenotype in Oncogenesis

Possible Route to the Multiple Mutations Seen in Later Cancer Stages

Evolutionary Dynamics of Mutator Phenotypes in Cancer: Implications for Chemotherapy, Natalia L. Komarova and Dominik Wodarz, 2003, Cancer Research, 63, 6635-6642. (Full text (HTML) and PDF versions of the article are available on the Cancer Research website.) PubMed ID: 14583456


Hypothetical Model of Chemoresistance in Human Ovarian Cancer Cells

Fraser et al. Reproductive Biology and Endocrinology 2003 1:66


In chemosensitive ovarian cancer cells (A), cisplatin increases p53, leading to upregulation of proteins promoting cell cycle arrest, e.g., p21, & pro-apoptotic proteins such as Bax & Fas. This activates both the intrinsic (mitochondrial) & extrinsic (death-receptor) apoptotic paths with the overall result being activation of the execution caspase-3 (& -7, not shown). In these cells, cell survival mediators such as Xiap, Akt, and Flip (in red) are downregulated or are in their inactive state. Prohibitin may also play a role in inhibiting cell cycle progression via the Rb-E2F pathway by binding Rb. In a chemoresistant cell (B), increased p53 ubiquitination by MDM2 results in maintenance of low levels of p53, despite the presence of cisplatin. Also, cisplatin fails to downregulate Xiap, thereby maintaining an active state of the PI3K/Akt pathway, & binding of TNFR2 by TNFα leads to upregulation of FLIP through the NFκB pathway, thus inhibiting the pro-apoptotic actions of NFκB through TNFR1. Overall, because the caspase cascade now fails to be activated by the chemotherapeutic agent, these cells lose their capacity to undergo apoptosis. They have become chemoresistant.

stages of tumour development

Malignant cell

Stages of tumour development






Vasculartargeting agents


EGFR inhibitorsHER2 antibodies









of other organs

of other organs



Stages & Mechanisms:

Breast & Colon Cancer

breast cancer continuum intervention possibilities


< 1cm


Late StageCancer


of Breast


Women at



1.7 % to





LCIS 6.5%

ADH 5.1%




DCIS 7.2%

Early Stage

node neg


Early Stage

node pos


Breast Cancer Continuum: intervention possibilities

Prevention of Progression

Prevention of Recurrence

Prevention of Contralateral Breast Cancer 3.2%

Prevention of ClinicallyDetectable Breast Cancer

breast cancer staging
Breast Cancer staging

With thanks to Professor W.Jonat

breast cancer staging 2
Breast Cancer staging 2

With thanks to Professor W.Jonat

breast cancer staging 3
Breast Cancer staging 3

With thanks to Professor W.Jonat



Janknecht Laboratory , Mayo Clinic


Normal Arrangement of Elements of an Epithelium

The multiple layers between the epithelial cells & the vasculature must be breached for a cancer to become metastatic.


Progression of Colon Cancer

National Cancer Institute


Video Links for Other Lectures or Film Loops on Carcinogenesis, the Cell Cycle & Endocrinology

General Site (multiple films):

Putting the Breaks on Cancer (Vogelstein, Johns Hopkins University):